Salts of physiologically active and psychoactive alkaloids and amines simultaneously exhibiting bioavailability and abuse resistance

ABSTRACT

Drug substances comprising a pharmaceutically acceptable organic acid addition salt of amine containing pharmaceutically active compounds useful for the treatment of a therapeutic ailment administration and exhibiting prophylactic properties when employed in non-therapeutic administration.

CROSS-REFERENCE TO COPENDING APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 11/595,379 filed Nov. 10, 2006 now U.S. Pat. No.7,718,649 issued May 18, 2010 and is also a divisional application ofabandoned U.S. patent application Ser. No. 11/805,225 filed May 22,2007.

BACKGROUND OF THE INVENTION

The present application is related to pharmaceutically acceptable saltsof alkaloids or amine containing compounds, particularly thoseexhibiting physiological and/or psychological activity in humans andsimultaneously designed for targeted release in a controlled pH range soas to eliminate or reduce the compound's physiological or psychologicalresponse when used in, or for, medically non-sanctioned, and/orillegitimate purposes. The invention embodies a platform technology forincorporating a targeted release mechanism within an organic-acidaddition salt of amine-containing pharmaceutically active compounds.More specifically, many final dose drug products are formulated withactive pharmaceutical ingredients (drug substances) that provide painrelief, mood alteration or modification, sense of euphoria, analgesia,sedation, or in addition, affect a psychotropic response. These drugproducts most often have the highest probability of abuse. As discussedherein, abuse means human use of physiologically or psychologicallyactive compounds for purposes than otherwise intended or legallyprescribed. As an example, the drug product Oxycontin® contains the drugsubstance oxycodone hydrochloride. The U.S. Drug Enforcement Agency(DEA) recognizes Oxycontin® as being implicated in a huge number of drugabuse cases resulting in a substantial societal impact. Beyond the humansuffering emanating from drug abuse, the financial costs to society area well-known burden shared by all citizens. The method of abuse, oncethe drug product is obtained (usually by illegal means), is to removeany coating on the tablet (often by lemon juice or saliva) followed bygrinding the remaining portion into a powder. The powder is then inhaledinto the nasal passageway (i.e. sniffed or “snorted”) to impart the“high” to the abuser. Alternatively, the powder can be extracted ormelted and the drug abuse performed by intravenous injection. Additionalroutes of administration for abusive purposes include the muscosalsurfaces (ocular, nasal, pulmonary, buccal, sublingual, gingival, rectaland vaginal mucosa).

Of significant seriousness with detrimental consequences to society isthe illicit production of methamphetamine (“meth”). Frequently,laboratories illegally producing meth are ill-equipped for the requiredsynthetic transformations and as a consequence, introduce significanthealth risks to the laboratory operators. Serious conflagrations andfires have resulted from poorly operated laboratories and theseincidents resulted in burn victims which in turn are overwhelming theresources of citizen-funded burn centers. Further, law enforcement isoften exposed to hazardous chemical situations and local environmentaldamage occurs because of the lack of containment of toxic and/orhazardous chemicals. Key raw materials used to produce “meth” includeephedrine and pseudoephedrine which are most often found as the activeingredient in legitimate, useful cough and cold, and allergy medicines.Pseudoephedrine or ephedrine is easily extracted from these medicines bypreferentially dissolving the active ingredient pseudoephedrinehydrochloride or ephedrine hydrochloride into, for example, isopropyl(“rubbing”) alcohol followed by isolation and recovery by evaporation ofthe solvent. These beneficial products are now receiving more scrutinyand market restriction because of their illicit use to manufacturemethamphetamine, “meth”.

In a report dated July 2005 from the National Center on Addiction andSubstance Abuse (CASA) at Columbia University and entitled “Under theCounter: The Diversion and Abuse of Controlled Prescription Drugs in theUS”, a recommendation was extolled for the FDA to require controlleddrug manufacturers to take measures, where possible, to minimize theabuse potential of the drugs they manufacture. The suggested route foraccomplishing this task was to formulate or reformulate the drugproducts to retain the desired therapeutic effect while preventingabuse. Also contained within the report are the disturbing datarepresenting severe societal repercussions that in the period 1992 to2003, drug abuse cases increased seven times faster than the increase inthe US population.

Prior to the CASA report, the pharmaceutical industry recognized theseverity of the drug abuse problem and innovative techniques to mitigateor control non-medical uses of drug substances and products have beenpublished. Essentially, three mechanisms have been reported whichminimize the potential for drug abuse: 1) encase within the drugproduct's formulation an antagonist to the drug substance, 2) chemicallymodify the drug substance to yield a prodrug, and 3) employ formulationtechniques to yield products resistant to drug abuse.

The combination product wherein the drug substance prone to abuse issimultaneously delivered with an antagonist which is activated onlyunder special circumstances typically employed by abusers (crushing,chewing, or dissolving) has received significant attention. Successfulclinical trials were announced by the company Alpharma and reported inFDAnews Drug Pipeline Alert™ (Volume 4, No. 193, Oct. 3, 2006). Thecapsule formulation consists of an extended-release opioid with asequestered core of naltrexone, an opioid antagonist. The sequesteringsubunit enabling this technology is described by Boehm in United StatesPatent Application Publication US 2004/01341552 A1, and is totallyincorporated herein by reference.

Similarly, Elite Pharmaceuticals is reportedly initiating a Phase IIclinical trial of its abuse resistant pain drug also employing theantagonist naltrexone hydrochloride. The report found in FDAnews DrugPipeline Alert™ (Volume 4, No. 179, Sep. 13, 2006) states the previousPhase 1 trial confirmed the technical approach such that when the drugproduct was taken as intended, no antagonist was measured in the bloodstream. However, if the drug product was crushed, the antagonist wasreleased into the blood stream and the euphoria normally experience byoxycodone hydrochloride abusers was reduced.

Alternatives to the preceding agonist/antagonist approach include thepreparation of prodrugs that exhibit their therapeutic value only whenused for their intended purpose. Buchwald, et al. in United StatesPatent Application Publication (US 2004/0058946 A1), the disclosure ofwhich is totally incorporated herein by reference, identifies modifiedoxycodone derivatives (prodrug) such that its physiological activity isonly observed after the prodrug is converted to the drug in themammalian gastrointestinal tract. Mickle, et al. in United States PatentApplication Publication (US 2005/0266070 A1), the disclosure of which istotally incorporated herein by reference, identifies hydrocodoneconjugates that release the drug substance following oral administrationyet are resistant to intravenous or intranasal abuse.

Similarly, U.S. Pat. No. 7,105,486 B2 (Mickle et al.) the disclosure ofwhich is totally incorporated herein by reference, describes thecovalent attachment of L-lysine to the drug substance, amphetamine, toprovide compounds and compositions exhibiting abuse-resistant propertiesand useful for the treatment of disorders including attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),narcolepsy and obesity.

In regard to formulation techniques, Vaghefi, et al. in United StatesPatent Application Publication (US 2006/0104909 A1), the disclosure ofwhich is totally incorporated herein by reference, describes thecreation of a matrix of discrete particles within which an activeingredient susceptible to abuse is distributed. The particles are coatedwith a water insoluble coating material creating the matrix from whichthe active ingredient is difficult to separate. The methodology providesa controlled release pharmaceutical composition having a reducedpotential for abuse.

Another formulation technique is described in Unites States PatentApplication Publication US 2006/0051298 A1, (Groenewoud), the disclosureof which is totally incorporated herein by reference. The abuseresistant pharmaceutical dosage consists of an active ingredient and atleast one gel forming granule, and said granule possesses an outerbrittle coating. Should the outer coating be crushed (for the purpose ofabusing the drug), the subsequent exposure to an aqueous media creates agel and inhibits extraction of the active ingredient.

Yet another formulation technique, but from the perspective of utilizingan agonist, is described in U.S. Pat. No. 4,622,244 (Lapka et al.), thedisclosure of which is totally incorporated herein by reference. InLapka et al. the inventors recommend the exposure of the drug substance,naltrexone pamoate, and a bioabsorbable polymer material to humiditybefore a microencapsulation process occurs. The equilibration in a humidenvironment of a hydrophobic drug and other materials impacts importanteffects on the nature of the microcapsule thus formed.

Similarly, in U.S. Pat. No. 6,203,813 B1 (Gooberman), the disclosure ofwhich is totally incorporated herein by reference, the authors makereference to the controlled release of an opiate antagonist implant ofnaltrexone pamoate in a linear poly(ortho) ester.

The three mechanistic approaches presented above (antagonist, prodrugand formulation) attempt to address abuse potential by impacting theroute of administration, or to differentiate the physiologicalenvironment in which the drug fulfills its intended purpose versus thedrug's misuse. The release of the antagonist by illicit mechanical orphysical manipulations effectively “neutralizes” the attempted abuse bythe perpetrator. Alternatively, addiction could be treated by theimplant of a slow-release of an antagonist as in Gooberman. Afundamental disadvantage to this combination drug/anti-drug technologyis the presence of two drug substances in a product formulation forwhich an equivalent pharmacokinetic profile must fit potential users (orabusers) of the drug. There is also the added cost of the additionalantagonist. As a technology, the antagonist approach does not offer aplatform methodology to the many controlled substances having medicinalbenefit. While the opioids as a class may have readily availableantagonists (e.g naltrexone and naloxone), other controlled substancesmay not have effective antagonists. From a marketing and patientperspective, many perceived problems may arise particularly if thereliability or the intended effect of the drug is questioned.

In regard to the prodrug approach (for which not all abused drugs aresusceptible to this approach), elegant chemistry is employed as ananti-abuse technology. In this case, release of the drug substance iscontrolled by physiological, enzymatic cleavage of the covalently boundprotecting group attached to the drug substance. Theoretically, the drugis only released when the prodrug is in the intended environment for itsabsorption. Unfortunately, drug abusers and those illicitly supplyingdrugs for abuse understand free-basing techniques which are directlyapplicable to liberating a drug from its prodrug analog. Further thephysiological aspects of the prodrug may alter the drug's anticipatedpharmacokinetic profile and sufficient concentrations may not beavailable in certain patient populations to achieve the legitimatetherapeutic effect.

The third mechanism employed for providing abuse-resistant drug productsis through formulation techniques. Sophisticated manufacturingtechniques are employed to produce products whose anti-abuse mechanismrelies on forming a matrix from which the drug substance cannot easilybe extracted. As with all formulated products, content uniformitybecomes a dominating factor at the commercial scale. In the formulationprocess during commercial scale product manufacture, the assurance thateach individual dose is identical is of critical importance. The matrixtechnology has inherent limitations for achieving content uniformityfrom a chemical assay perspective. In addition, the anti-abuse propertymust be maintained for every single dosage presentation and performance(anti-abuse) uniformity is likely challenged. Here too, encasing thedrug in a matrix inherently alters the drug's pharmacokinetic profileand sufficient concentration may not be obtainable to achieve thedesired therapeutic effect.

Historically, the preparation of mineral acid salts of basic drugs hasbeen the preferred choice for imparting immediate releasecharacteristics to drug substances. A drug substance's dissolutionprofile can influence its absorption characteristics, and in the case ofa drug with a potential for abuse by snorting into the nasal cavity,rapid dissolution in nasal fluid would be required. Other factorsinfluencing the absorption of the drug include the physiological pHencountered, the drug substance's morphology, the particle size and theparticle size distribution. Typically, the nasal cavity pH is about 4.5which provides for the rapid dissolution and absorption of highlysoluble, mineral acid salts of drug substances.

U.S. Pat. No. 5,232,919 (Scheffler, et al.), the disclosure of which istotally incorporated herein by reference, discloses azelastine embonateand pharmaceutical formulations/compositions which contain it; theembonate salt to eliminate the bitter taste of azelastine alone. Theterm embonate is a synonym for pamoate.

French Patent 1,461,407 (Saias, et al.), the disclosure of which istotally incorporated herein by reference, discloses a process for thepreparation of amine pamoates where the amine component includespiperazine, promethazine, papaverine, pholocodine, codeine, noracotineand chlorpheniramine.

The United Kingdom Patent Specification No. 295,656, (Carpmaels &Ransford, agents for applicants) the disclosure of which is totallyincorporated herein by reference, discloses a process for themanufacture of difficulty soluble salts of organic bases and alkaloids.The disclosure further indicates the process for manufacture providessparingly soluble and tasteless salts of organic nitrogenous basiccompounds including alkaloids.

U.S. Pat. No. 3,502,661 (Kasubick, et al.), the disclosure of which istotally incorporated herein by reference, discloses a process for thepreparation of variously substituted pyridinium and imidazolines alongwith their acid addition salts. Some examples indicate pamoate saltswere prepared for select organic bases.

U.S. Pat. No. 2,925,417 (Elslager, et al.), the disclosure of which istotally incorporated herein by reference, discloses quinolinium salts ofpamoic acid and a process for their manufacture.

U.S. Pat. No. 5,776,885 (Orsolini, et al.), the disclosure of which istotally incorporated herein by reference, discloses a pharmaceuticalcomposition for the sustained and controlled release of water insolublepolypeptides whereby the therapeutically active peptide is in the formof its pamoate, tannate or stearate salt.

U.S. Pat. No. 5,445,832 (Orsolini, et al.), the disclosure of which istotally incorporated herein by reference, discloses a process for thepreparation of microspheres made of a biodegradable polymeric materialwhereby a water soluble peptide or peptide salt is converted into acorresponding water-insoluble peptide salt selected from pamoates,stearates or palmitates of the said peptide.

U.S. Pat. No. 5,439,688 (Orsolini, et al.), the disclosure of which istotally incorporated herein by reference, discloses a process forpreparing a pharmaceutical composition in the form of microparticlesdesigned for the controlled release of a drug that includes abiodegradable polymer and where the active ingredient can be selectedfrom a group of possible salts, one being a pamoate.

U.S. Pat. No. 5,271,946 (Hettche) the disclosure of which is totallyincorporated herein by reference, discloses a controlled releaseazelastine containing pharmaceutical composition whereby azelastine isincorporated into the formulation as its pamoate or otherpharmaceutically active salt.

U.S. Pat. No. 5,225,205 (Orsolini, et al.), the disclosure of which istotally incorporated herein by reference, discloses a pharmaceuticalcomposition in the form of micropoarticles; the formulation consistingof a peptide as its pamoate, tannate, stearate or palmitate salt; theformulation to provide a controlled release, pharmaceutical compositionfor the prolonged release of a medicamentous substance.

In spite of the long history of research directed at prohibiting theillicit use of pharmaceutical compounds the problem remains. There hasyet to be a suitable solution which is widely applicable, easilyimplemented and applicable to a wide range of active pharmaceuticalingredients. The present invention provides a platform technology toaddress this long standing problem.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method forsupplying a pharmaceutical formulation which is bio-available by an oraladministration route but is bio-unavailable when illicit orabuse-intended routes of administration are attempted.

It is another object of the present invention to provide a method forsupplying a pharmaceutical formulation which prohibits or impedesde-formulation to a degree sufficient to alter the manner in which theactive pharmaceutical ingredient can be absorbed physiologically beyondits intended, legal, absorption route.

It is another object of the present invention to provide apharmaceutical composition possessing anti-abuse characteristicsattributable to targeted release properties.

It is another object of the present invention to provide drug substancesand drug products having orthogonal dual property combinations wherein abinary differentiation is observed between the intended, or legal, andthe abusive, illegal/illicit, use of the drug substance or product. Thepatient receives the intended dosage when used properly, but the desiredeffect is not obtained if not used properly.

It is another object of the present invention to provide a method forsupplying a pharmaceutical formulation where the active pharmaceuticalingredient is resistant to direct extraction techniques either into anaqueous solution or into an organic solvent.

It is another object of the present invention to inhibit and/or preventde-formulation of a drug product by increasing the technical difficultyof isolating the active pharmaceutical ingredient from its carriermatrix such as excipients, binders and the like. This feature of theinvention further decreases the economic viability of isolating the APIfor illicit purposes.

It is another object of the present invention to provide drug productsemploying the pharmaceutical salt methodology described herein wherebythe potential for abuse of either the drug substance and/or the drugproduct is eliminated or greatly reduced when abuse is attempted via themucosal surfaces or by injection or by illicit de-formulation to allowuse via the muscosal surfaces or by injection.

These and other advantages, as will be realized are provided in a drugsubstance with a pharmaceutically acceptable organic acid addition saltof an amine containing pharmaceutically active compound useful for thetreatment of a therapeutic ailment administration and exhibitingprophylactic properties when employed in non-therapeutic administration.

Yet another embodiment is provided in a drug substance as apharmaceutically acceptable organic acid addition salt of an aminecontaining pharmaceutically active compound exhibiting at least twodissolution profiles one of which provides for drug efficacy whenadministered in a formulated oral dosage and one which does not providedrug efficacy when administered as a non-oral dosage.

Yet another embodiment is provided in a drug substance with an organicacid addition salt of an amine containing pharmaceutically activecompound used to treat a combination of two or more therapeuticailments, at least one of which is drug abuse.

Yet another embodiment is provided in the prescribing of a drug productcontaining at least one drug substance as an organic acid addition saltof an amine containing API to a patient by a defined method ofadministration wherein the drug substance is a prophylactic in adifferent method of administration.

Yet another embodiment is provided in the prescribing of a drug productcontaining at least one drug substance comprising an organic acidaddition salt of an amine containing active pharmaceutical ingredient toa patient for the purpose of treating an ailment by a specificadministration mechanism wherein the drug product is renderedineffective by a different administration mechanism.

Yet another embodiment is provided in prescribing a drug productcontaining at least one drug substance as an organic acid addition saltof an amine containing Drug Enforcement Administration controlledsubstance to a patient for the purpose of treating a legitimate ailmentof the patient wherein the patient has a history of drug abuse meaningthey have been clinically diagnosed as having drug abuse propensity.

Yet another embodiment is provided in prescribing a drug productcontaining at least one drug substance as an organic acid addition saltof an amine containing DEA controlled substance to a patient for thepurpose of treating a legitimate ailment while simultaneouslyinterrupting the potential for mental and physical addiction through thepatient inadvertently or deliberately using the drug substance for otherthan the intended purpose.

Yet another embodiment is provided in a process for preparing organicacid addition salts of amine containing pharmaceutically activecompounds comprising the steps of:

dissolving of an amine containing pharmaceutically active compound in asuitable solvent;

preparing a solution of an organic acid of Structure A

wherein R¹-R⁴ are independently selected from H, alkyl of 1-6 carbons,adjacent groups may be taken together to form a cyclic alkyl or cyclicaryl moiety;R⁵ is selected from H, or an alkali earth cation;R⁶ is selected from H, alkyl of 1-6 carbons, an alkali earth cation, andaryl of 6 to 12 carbons, in a number sufficient to complete the valencebonding of X, and wherein X is selected from nitrogen, oxygen or sulfur,combining the solutions of amine containing pharmaceutically activecompound, and the organic acid to form the reaction mixture wherein saidorganic acid has at least one mole of organic acid per mole of aminecontaining pharmaceutically active compound;allowing said reaction mixture to react;isolating said organic acid salt of amine containing pharmaceuticallyactive compound by filtration, centrifugation or concentration, anddrying the isolated or purified material to remove reaction solvent.

Yet another embodiment is provided in a process for preparing theorganic acid addition salts of amine-containing pharmaceutically activecompound exhibiting targeted release properties comprising the steps of:combining a pH adjusted solution of said amine-containingpharmaceutically active compound with an organic acid having at leastone aromatic ring and possessing carboxyl and hydroxyl functionality inan ortho relationship or their synthetic equivalent to form a reactionsolution;

cooling and precipitating solids from said reaction solution;

collecting said precipitated solid; and

drying said solids.

Yet another embodiment is provided in a process for preparing apharmaceutically acceptable drug product exhibiting drug abuseprevention properties comprising the steps of:

selecting an organic acid addition salt of an amine containing activepharmaceutical ingredient,

combining the organic acid salt with excipients and processing aids toyield a mixture;

mixing the combined ingredients to provide blend uniformity;

sieving, screening or milling the mixture to obtain a uniformconsistency; and

adding ingredients to the mixture for desired proportions of eachingredient to yield a final formulated mix.

Yet another embodiment is provided in an organic acid addition salt ofamine-containing pharmaceutically active compounds wherein the organicacid comprises a compound of Formula A:

wherein R¹-R⁴ are independently selected from H, alkyl of 1-6 carbons,adjacent groups may be taken together to form a cyclic alkyl or cyclicaryl moiety;R⁵ is selected from H, or an alkali earth cation;R⁶ is selected from H, alkyl of 1-6 carbons, an alkali earth cation, andaryl of 6 to 12 carbons, in a number sufficient to complete the valencebonding of X, and wherein X is selected from nitrogen, oxygen or sulfur.

Yet another embodiment is provided in organic acid addition salts ofamine-containing pharmaceutically active compounds selected for theirtargeted release characteristic in the gastro intestinal tract andbio-unavailability in mucosal membranes, and formulated into a drugproduct wherein the amine-containing pharmaceutically active compoundscan not be directly isolated.

Yet another embodiment is provided in a tamper resistant oral dosagedrug product comprising an organic acid salt of an amine-containingpharmaceutically active compound formulated wherein said organic acidand said amine-containing pharmaceutically active compound can not bedirectly isolated.

Yet another embodiment is provided in a method of administering anamine-containing pharmaceutically active compound formulationcomprising: preparing an organic acid salt of said compound;

preparing an oral dose formulation comprising said organic acid salt;

wherein upon oral digestion said compound forms a bio-availableamine-containing pharmaceutically active compound; and

wherein upon use for administration via a mucosal membrane saidamine-containing pharmaceutically active compound is ineffective.

Yet another embodiment is provided in a pharmaceutically active compoundcomprising the organic acid addition salt of an amine-containingpharmaceutically active material wherein the compound is essentiallybio-unavailable when exposed to mucosal membranes and exhibits recoveryfrom aqueous solution at pH 4.5 of at least 85 weight percent.

Yet another embodiment is provided in a pharmaceutically active compoundcomprising the organic acid addition salt of an amine-containingpharmaceutically active material wherein the compound is essentiallybio-unavailable when exposed to human mucosal membranes and exhibitsrecovery from aqueous solution at pH 7.0 of at least 85 weight percent.

Yet another embodiment is provided in a pharmaceutically active compoundcomprising an organic acid addition salt of an amine-containingpharmaceutically active material wherein the compound is essentiallybio-unavailable when exposed to mucosal membranes unless processed bythe steps of:

dissolution in an aqueous solution of pH greater than 8;

extraction of the active pharmaceutical ingredient into a waterimmiscible solvent;

separation of the aqueous layer from the solvent;

washing of the solvent layer with an aqueous solution of pH greater than8; and

drying the solvent layer to remove traces of water.

Yet another embodiment is provided in a pharmaceutically active compoundcomprising an organic acid addition salt of an amine-containingpharmaceutically active material wherein the compound is essentiallybio-unavailable when exposed to mucosal membranes unless processed bythe steps of:

dissolution in an aqueous solution of pH greater than about 1;

filtration of the precipitated organic acid;

adjustment of the filtrate to a pH of about 8;

addition of a water immiscible solvent in which the pharmaceuticallyactive compound is soluble;

separation of the aqueous layer from the solvent;

washing of the solvent layer with an aqueous solution of pH greater than8; and

drying the solvent layer to remove traces of water.

Yet another embodiment is provided in the use of a drug productcontaining at least one drug substance as an organic acid addition saltof an amine containing DEA controlled substance wherein oraladministration of the drug substance provides an efficacious dosage andnon-oral administration does not provide an efficacious dosage.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is an DSC thermogram of phentermine pamoate.

FIG. 2 is an DSC thermogram of ephedrine pamoate.

FIG. 3 is an DSC thermogram of pseudoephedrine pamoate.

FIG. 4 is an FTIR spectrum phentermine pamoate.

FIG. 5 is an FTIR spectrum of ephedrine pamoate.

FIG. 6 is an FTIR spectrum of pseudoephedrine pamoate.

FIG. 7 is an PXRD diffractogram of phentermine pamoate.

FIG. 8 is an PXRD diffractogram of ephedrine pamoate.

FIG. 9 is an PXRD diffractogram of pseudoephedrine pamaote.

FIG. 10 is an DSC thermogram of benzphetamine pamoate.

FIG. 11 is an FTIR spectrum benzphetamine pamoate.

FIG. 12 is an PXRD diffractogram of benzphetamine pamoate.

FIG. 13 is an DSC thermogram of imipramine xinafoate.

FIG. 14 is an FTIR spectrum of imipramine xinafoate.

FIG. 15 is an ¹H NMR spectrum of imipramine xinafoate.

FIG. 16 is an DSC thermogram of imipramine salicylate.

FIG. 17 is an FTIR spectrum of imipramine salicylate.

FIG. 18 is an ¹H NMR spectrum of imipramine salicylate.

FIG. 19 is a graphical presentation of the dissolution profilecomparison of imipramine pamoate vs. imipramine hydrochloride undersimulated gastric conditions.

FIG. 20 is a graphical presentation of the dissolution profilecomparison of imipramine xinafoate vs. imipramine hydrochloride undersimulated gastric conditions.

FIG. 21 is a graphical presentation of the dissolution profilecomparison of imipramine salicylate vs. imipramine hydrochloride undersimulated gastric conditions.

FIG. 22 is a graphical presentation of the dissolution profilecomparison of ephedrine pamoate vs. ephedrine hydrochloride undersimulated gastric conditions.

FIG. 23 is a graphical presentation of the dissolution profilecomparison of pseudoephedrine pamoate vs pseudoephedrine hydrochlorideunder simulated gastric conditions.

FIG. 24 is a graphical presentation of the dissolution profilecomparison of benzphetamine pamoate vs. benzphetamine hydrochlorideunder simulated gastric conditions.

FIG. 25 is a graphical presentation of the dissolution profilecomparison of phentermine pamoate vs. phentermine hydrochloride undersimulated gastric conditions.

FIG. 26 is a graphical presentation of the release profile of imipraminehydrochloride vs. imipramine pamoate under gastric conditions comparedto release under mucosal conditions.

FIG. 27 is a graphical presentation of the release profile of imipraminehydrochloride vs. imipramine xinafoate under gastric conditions comparedto release under mucosal conditions.

FIG. 28 is a graphical presentation of the release profile of imipraminehydrochloride vs. imipramine salicylate under gastric conditionscompared to release under mucosal conditions.

FIG. 29 is a graphical presentation of the release profile of ephedrinehydrochloride vs. ephedrine pamoate under gastric conditions compared torelease under mucosal conditions.

FIG. 30 is a graphical presentation of the release profile ofpseudoephedrine hydrochloride vs. pseudoephedrine pamoate under gastricconditions compared to release under mucosal conditions.

FIG. 31 is a graphical presentation of the release profile ofbenzphetamine hydrochloride vs. benzphetamine pamoate under gastricconditions compared to release under mucosal conditions.

FIG. 32 is a graphical presentation of the release profile ofphentermine hydrochloride vs. phentermine pamoate under gastricconditions compared to release under mucosal conditions.

DETAILED DESCRIPTION

The invention disclosed herein provides an entirely new mechanism forproviding abuse resistant drug substances and drug products whereby themethod of inhalation, smoking, intravenous injection, and mucosalsurface abuse is eliminated or reduced by forming an organic acidaddition salt of the active ingredient having release propertiesincompatible with the normal administration routes for drug abuse andemploying a targeted release mechanism. This platform technology iswidely applicable to amine containing alkaloid drug substances includingbut not limited to those drug substances categorized by the DEA asControlled Substances. To elaborate on the invention's mode of action,but without relying on any particular theory or principle, drugs thatare abused require that the active ingredient be bio-available in themucosal membranes and particularly the ocular, nasal, pulmonary, buccal,sublingual, gingival, rectal or vaginal mucosa. In effect, a drug mustfirst be released and have sufficient permeability in its biologicalenvironment for it to be bio-available. Therefore, by altering thedissolution profile to restrict, limit, reduce or eliminate release ofthe drug substance at physiological pH the potential for abuse isdecreased. Simply stated, the drug cannot be abused without involved andtechnically sophisticated chemical transformations and isolation priorto the behavioral act of drug abuse. Simultaneously, the invention asdescribed serves valuable and beneficial purposes in society bypreventing drug abuse yet the invention retains the medicinal propertiesof the drug product when used for the intended purpose. The followingdiscussion illustrates the design features for producing commercial drugsubstances and products. The benefits of the present invention are thosedescribed above and can be practiced while retaining the complexrequirements reviewed below.

Independent of the route of administration, it is axiomatic that a drugsubstance must be bio-available in its intended physiologicalenvironment in order for it to elicit the desired pharmaceutical effect.Indeed, the number of pharmaceutical products based on insoluble aminesalts is very limited and not surprisingly, the pharmaceuticalliterature describing the absorption benefits of otherwise insolubleamine salts is essentially non-existent. Basically, the literatureteaches that higher solubility in general implies betterbio-availability. While entirely speculative, the use of insoluble saltswas probably avoided because practitioners of the art incorrectlycorrelated poor API aqueous solubility with poor bio-availability.Indeed, the commercial success of mineral acid salts of amine-containingAPIs suggests a negative teaching away from insoluble salts. Anunexpected observation and correct correlation pertaining to the currentinvention is that selective, or engineered API aqueous releaseproperties inhibits illicit use, or drug abuse, of the API and itsassociated products while retaining the bio-availability when employedfor its intended purpose. And indeed, these features can be provided byemploying a host of organic acids.

The actual basis for the invention is more complex than an insolubilityfeature of an API pamoate salt (or associated family of organic acidsalts). As mentioned in the introduction and as will be shown in theexperimental section and associated figures, the dissolution behavior ofthese organic acid salts of amine-containing APIs provide theunanticipated observation that these compounds can be employed intargeted release applications, and in particular to address drug abuse.As performed according to test procedures recognized by the UnitedStates Food and Drug Administration and documented within the UnitedStates Pharmacopeia (USP), dissolution properties are established as afunction of time, temperature, concentration and pH. In particular, onetest established the saturation solubility of the drug substance and isperformed over a pH range to correlate with the physiological pH rangesthe drug may encounter during use. For instance, the test employs a pHof about 1 to represent simulated gastric fluid. At the other end of therange, a pH of about 7.4 is employed to represent blood pH. IntermediatepH's are also tested to evaluate the drug's dissolution properties overthe entire range.

The present invention is applicable to a variety of drug deliverypresentations including solid oral dose, parenteral dosage forms(depo-type products) and by devices and formulations suitable fortransdermal delivery and nasal/inhalation administration. It isresponsibly acknowledged that many factors may influence the overallpharmacokinetic profile of a drug product, for instance, the particlesize distribution of the drug substance may markedly influence drugsubstance bioavailability. Hence, the optimum practice of this inventionwhen employed for a specific drug product must account for the multitudeof additional factors. The benefit of the current invention is a meansto provide a dominating or controlling factor to prevent abuse whileachieving efficacious and therapeutic patient dosages to whichrefinements, adjustments or modifications can be asserted to yield anoptimal response.

The three alternate mechanistic approaches presented earlier,(antagonist, prodrug and formulation, attempt to address abuse potentialby impacting the route of administration, or to differentiate thephysiological environment in which the drug fulfills its intendedpurpose versus the drug's misuse. Each of these routes was shown topossess inherent limitations for mitigating drug abuse. For the purposesof additional clarity and completeness, the mineral acid salts, whichare typically abused, do not exhibit a suitable means to prevent abuse.The dissolution properties of the mineral acid salts of thephysiologically active and/or controlled substance amines consistentlyexhibit high dissolution rates and substantial achievable release rates(85-100%) over the entire physiological pH range.

In contrast, it is relevant to the present invention to note theimportance of pH in controlling the release of a drug substance from itsproduct formulation to achieve absorption and consequently, themedicinal effect. The pH of the gastrointestinal tract essentiallyremains highly acidic with the exception of the lower colon whichreaches pH 8; vaginal pH is typically around 5.8 and the nasal cavity isapproximately pH 4.5. More generally, each of the mucosal surfaces,particularly ocular, nasal, pulmonary, buccal, sublingual, gingival,rectal and vaginal are receptive to drug absorption if release canoccur. A dominating feature of the present invention is the severelyretarded release of the controlled substance, particularlyamine-containing pamoate salt (or related salt family) in the pH rangeof about 4 to 9 which encompasses the physiological pH of the mucosa.These release properties were an unexpected finding recognized andobserved after performing dissolution tests over a wide pH range onseveral unrelated compounds. The release properties and saturationsolubility profiles are a means to evaluate a reasonable dosageapplication to the mucosa. The non-release of the drug in the 4 to 9 pHrange negates absorption and prevents the physical act of abuse. For theamine-containing hydrochloride salts, an abuse mechanism remainsoperative since these salts do not exhibit the discriminating “on/off”switch of the present invention.

An experimental refinement of the dissolution tests was performed onseveral compounds to better represent the physiological conditionsencountered during abuse attempts and to account for the saturationsolubility factor. Further, control experiments were included in theexperimental design to compare the organic acid addition salts of thecurrent invention with the hydrochloride salts of identicalamine-containing controlled substances. In some cases, model compoundswere used to demonstrate the principles of the invention instead ofusing compounds legally designated as controlled substances.Side-by-side dissolution experiments on hydrochloride salts versus thoseof the present invention were conducted at three different pHconditions: a) a pH of about 1 to simulate gastric conditions, b) pH ofabout 4.5 to simulate mucosal surface pH, and c) a pH of about 7 toevaluate a potential pH range of mucosal surfaces and blood pH forpurposes of simulating injection. In addition, the experimentation wasdesigned to demonstrate the equivalence of the organic acid additionsalts to the mineral acid salts if used by their intended route of oraladministration route and hence the concentration effects were includedin the study. For oral administration of a dosage form, the UnitedStates Pharmacopeia (USP) recommends the immediate release testingprocedure on a unit dosage to be performed on a simulated stomach“solution” volume of 900 mL. For the mucosal membranes, the availablemucous fluid may be better approximated at 10 mL. Hence, dissolutiontests were conducted at different concentrations at the different pHlevels. Besides temperature, pH and concentration, the time factor wasalso evaluated under the presumption that an individual abusing a drugwill want to obtain their anticipated physiological response within anhour.

It was observed that the organic acid addition salts under simulatedmucosal conditions were not released whereas the hydrochloride saltsreleased rapidly (refer to FIGS. 26-32). Therefore, recovery studiesfrom the simulated mucosal environments were more appropriate fordemonstrating the inability of the organic acid salt to release theactive ingredient and thereby prevent a physiological response.Therefore, the abuse mechanism was inoperative. For simulated gastricingestion, the organic acid addition salts exhibited a release propertyduring dissolution testing essentially equivalent to the hydrochloridesalts' dissolution properties in that both presentations wereessentially immediately available (refer to FIGS. 16 through 25). Tosummarize the trends, the organic acid addition salts were highlyavailable for absorption at gastric pH. Secondly, the organic acidaddition salts exhibit a low release rate under mucosal conditions. Andlastly, the organic acid addition salts exhibit a low level of releaseunder the mucosal conditions (see FIGS. 26-32). These definitiveexamples support the present invention's duality of providing an abusecontrolling mechanism and yet retaining the desired medicinal benefit ofthe drug substance when used in the intended manner.

For confirming tests and to demonstrate general applicability of thetargeted release properties of the amine-containing organic acidaddition salts, a model compound was selected to challenge thehypothesis. Imipramine was chosen as a representative amine-containingcompound for study comparison of its hydrochloride and organic acidaddition salts, namely pamoate, xinafoate and salicylate salts. Theselection of imipramine was based on practical considerations sinceworking with controlled substances has legal and moral responsibilitiesand imipramine fulfilled the structural features associated with manyamine-containing controlled substances. These structural features ofteninclude: at least one nitrogen; at least one aromatic ring; ideally themulti-ring/fused ring/heterocyclic sub-structures observed in manycontrolled substances; lipophilicity as the free base; the salts exhibitsufficient stability for the duration of the test regimens so as tominimize interference and potentially incorrect conclusions attributedto degradation products or impurities and the various salts employed inthe tests could be readily synthesized and characterized. Clearly, thecontrolled substance designation to an amine-containing compound havingphysiological activity is a legal assignment/assessment and has littleto no relevance to chemical structure or physical behavior. Hence, thescope of the invention is well supported by the selection of controlledand non-controlled substances exhibiting structural variation toevaluate the novel and unexpected observations disclosed herein.

Also disclosed herein are processes for the preparation of drugsubstances and DEA controlled drug substances (APIs) using organic acidaddition salts of the active pharmaceutical ingredient (API) which areoptionally formulated with other non-therapeutic materials to aid indelivery, stability, efficacy, targeted release and to engineer apharmacokinetic profile of the organic acid addition salts as comparedto other salt forms, including inorganic (mineral) acid salt forms. Thepresent invention provides for release of the API for its intendedpurpose and prevents availability of the drug substance for typicalroutes of abuse. The present invention describes a method forevaluating, and formulations for, the organic acid addition salts ofappropriate APIs to provide an efficacious and therapeutic dosage toanimals and humans.

The present invention practically and financially thwarts efforts toconvert drug substances to their corresponding mineral acid salt(s).This severely restricts, limits, reduces or eliminates the efforts ofpurposeful de-formulation of commercially available drug products into aform suitable for physiological absorption in a manner different thanintended by the original commercial formulation. The drug substancecannot be easily modified for alternate routes of administration withoutnumerous, involved and technically sophisticated chemicaltransformations and isolations. Simultaneously, many of these drugproducts prone to abuse serve valuable and beneficial purposes insociety and the invention retains the properties of the drug product(and in some cases enhances them) when used for the intended purpose.The benefits of the present invention are those described above and canbe practiced while retaining the complex requirements reviewed below.

A drug formulation which is selected for the prevention of drug abuse isspecifically a drug which is bio-unavailable or not isolable if effortsto alter the intended or established route of administration areundertaken. In a preferred embodiment the drug formulation is notreleased under aqueous conditions at a pH of about 4 to about 9 andgenerates a solid of an organic acid at pH below about 4. At pH aboveabout 9, the organic acid (as its inorganic salt) and the aminecontaining active pharmaceutical ingredient (as its free base) aresufficiently soluble as to prevent separation of the components and thusinhibiting direct isolation of the API (as its free base) withoutadditional processing.

In the present invention a drug product can be prescribed andadministered in a manner wherein proper administration provides atherapeutic effect and the function of the API is realized. With adifferent manner of administration, in other words, a non-therapeuticadministration the API does not enter the bloodstream in an amountsufficient to be active. To be effective the API must be bio-available.For the purposes of the present invention, one method of establishing acompound's bio-availability is by determining the percentage of weightAPI recovered from an aqueous solution at a pH representative of themethod of administration described herein. For the purposes of thepresent invention a compound is considered to be effective when at least85 wt % of the compound is recovered from an aqueous solution at a pHrepresentative of the method of administration. If, for example, 85weight percent or more of a drug compound is recovered from a solutionat a pH of 4-9, pH 7 for example, the material is considered to bebio-unavailable at a mucosal membrane and is considered non-permeable atthe mucosal membrane and the compound exhibits prophylactic properties.If, for example, less than 85 weight percent of a drug compound isrecovered from a solution at a pH of less than 4, pH 1 for example, thematerial is considered to be bio-available under oral administration andis considered permeable in, for example, the gastrointestinal tract dueto the release of the API at the pH of the gastrointestinal tract.

A particularly preferred embodiment and method of administering theamine-containing pharmaceutically active compound is by oral dose. Theoral dose is prepared by first preparing an organic acid salt of theactive compound. The organic salt is then formulated into a carriermatrix to provide an oral dose drug product. The carrier matrix iscomposed of ingredients (excipients) optionally selected from the group,but not limited to binders, fillers, flow enhancers, surfactants,disintegrants, buffers, and the like, typically employed in the art andfound in the “Handbook of Pharmaceutical Excipients”, Rowe, Sheskey andOwen (Editors), Fifth Edition, 2006, Pharmaceutical Press (publishers).When the oral dose is ingested the organic salt dissociates underphysiological conditions. The organic acid portion of theamine-containing organic acid addition salt forms the insoluble(organic) acid while the active compound is liberated and becomesbio-available. Efforts to directly isolate the active compound from theoral dose would be thwarted as described herein.

A common technique for de-formulating drug products, particularly forillicit use, is to isolate the active ingredient by organic phaseextraction and separation from an aqueous environment. An example ofsuch illicit activity is extraction of highly soluble ephedrinehydrochloride or pseudoephedrine hydrochloride with isopropanol, whichis more commonly known as rubbing alcohol. In an embodiment of thepresent invention, both pseudoephedrine pamoate and ephedrine pamoateand their related family of salts are insoluble in isopropanol and otherorganic solvents such as acetone and toluene.

In an embodiment of the present invention, the controlled substance isan amine-containing organic salt which does not release in the pH windowof about 4 to about 9. At a pH of less than about 4, the subject organicsalts become protonated with the concomitant precipitation of organicacid. At pH greater than about 9, the addition salt is soluble yet it isquite difficult to distinguish between the organic acid component andthe active amine by organic solvent extraction.

The organic acids of the present invention are those forming salts withamine-containing active pharmaceutical ingredients which do not releasein an aqueous solution within a pH window of about 4 to about 9 andwhich interfere with the direct isolation of the API outside of thecentral pH window.

The organic acid is defined by the following Structures A through Gwherein Structure A represents the general family of Markush compoundsembodied within the invention. Structure B represents the subset ofsalicylic acid and its derivatives conceived as a component of thisinvention. Structures C, D and E are regio-isomeric variations onCompound A wherein two adjacent substituents on Compound A form a fusedaryl ring (i.e. R¹+R²; R²+R³; and R³+R⁴). Structures F and G represent afurther sub-category of dimer-like compounds derived from Structure A.In Structure F, dimerization has occurred through R⁴ of two Structure Acompounds with both possessing fused-aryl ring systems formed via R²+R³.In Structure G, dimerization has again occurred through R⁴ of twoStructure A compounds however both Structure A residues possessfused-aryl ring systems formed via R¹+R².

Wherein R¹-R⁴ are independently selected from H, alkyl of 1-6 carbons,adjacent groups may be taken together to form a cyclic alkyl or cyclicaryl moiety; R⁵ represents H, alkyl, alkylacyl or arylacyl; R⁶ and R⁷are independently selected from H, alkyl of 1-6 carbons, aryl of 6-12carbons, alkylacyl or arylacyl analogues sufficient to satisfy thevalence of X (e.g. to provide a mixed anhydride or carbamate); X isselected from nitrogen, oxygen or sulfur, and when X═O, R⁶+R⁷ mayrepresent an alkali earth cation, ammonium or together form aheterocyclic moiety;

Particularly preferred organic acids include Structures B through E.

wherein R⁵, R⁶ and R⁷ remain as defined above for Structure A;

wherein X, R⁵, R⁶ and R⁷ remain as defined above for Structure A andmore preferably X is O;

wherein X, R¹, R², R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O; R¹ and R² are hydrogen;

wherein X, R¹, R⁴, R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O, R¹ and R⁴ are hydrogen;

wherein X, R¹, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably at least one X is O and at least one R¹is hydrogen; and

wherein X, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably X is O and R⁵ is hydrogen.

Pamoic acid, or a synthetic equivalent of pamoic acid, is the preferredembodiment. Pamoic acid has a formula corresponding to Structure Fwherein X is O; R⁵, R⁶ and R⁷ are hydrogen.

A synthetic equivalent of pamoic acid is a material that provides thestructural moiety independent of its particular salt, ester, or amideform and that upon pH adjustment yields pamoate functionality suitablefor reaction, optionally with one or two equivalents of anamine-containing active pharmaceutical ingredient to form a pamoatesalt. Examples of synthetic equivalents of pamoic acid capable ofmanipulation to produce pamoate salts include but are not limited to,disodium pamoate, di-ammonium pamoate, di-potassium pamoate, lowermolecular weight di-alkyl and/or di-aryl amine pamoate, lower molecularweight di-alkyl and/or di-aryl esters of pamoic acid, and lowermolecular weight di-alkylacyl and/or di-arylacyl O-esters of pamoicacid, i.e. those alkylacyl and arylacyl esters formed using the hydroxylmoiety of pamoic acid and not the carboxylic acid functional group. Thedescriptor phrase “lower molecular weight” used above means theindicated moiety has a molecular mass contribution within the pamoatederivative of less than about 200 amu.

For clarity, the use of lower molecular weight di-alkyl or di-aryl aminepamoate allows for the exchange of higher molecular weight amines, ordrug free bases, to be exchanged for the lower molecular weight aminecomponent during the salt formation reaction. Similarly, the use oflower molecular weight di-alkylacyl and/or di-arylacyl pamoates allowfor their conversion through ester hydrolysis to the pamoic/pamoatemoiety followed by reaction with the desired drug free base.

In a preferred embodiment of the invention, at least one equivalent ofthe amine containing drug substance is reacted per mole of disodiumpamoate to yield the drug substance pamoic acid salt. Preferably, 2:1,1:1, or mixtures thereof, equivalents of amine per mole pamoic acidmoiety or related organic acids are prepared. Typically, an aqueousacidic solution of the amine containing drug substance is combined witha basic solution of pamoic acid or disodium pamoate. The acid/basereaction ensues and the insoluble organic acid salt precipitates fromthe aqueous solution. Optionally, the salt can be purified, dried andmilled to obtain a drug substance ready for formulation into the desireddelivery format. The drug product formulated with the drug substancesthen possesses the targeted delivery characteristics of the drugsubstance and the potential for abuse of either the drug substanceand/or drug product is eliminated or greatly reduced when abuse isattempted via the mucosal surfaces or by injection.

Another feature of the invention is the preparation of pamoate salts forlegitimate active pharmaceutical ingredients wherein the activepharmaceutical ingredient is otherwise used as a synthetic raw materialin the illegal or illicit production of dangerous drugs. Morespecifically, the invention encompasses the preparation and compositionof pseudoephedrine pamoate and ephedrine pamoate. The insolubility ofthese compounds in organic solvents thwarts attempts to extractpseudoephedrine and/or ephedrine from drug products. These compoundswhen subjected to the illicit activities of methamphetamine production,a first step of which is to attempt extraction of the pseudoephedrinepamoate or ephedrine pamoate from tablets or capsules usually with analcohol solvent, results in an intractable residue of insolubleexcipients and pseudoephedrine pamoate or ephedrine pamoate. Here too,the pamoate salts are for illustration and a broader family of organicacid salts (vide supra) may be employed for practicing the invention.

For the purposes of the present invention an API of a drug product isnot directly isolable if it can not be isolated by solubilizing the drugproduct to form a solubilized drug substance and filtering thesolubilized drug substance without further chemical processing.

Another feature of the invention addresses a significant commercial andlong-felt need to return the availability of traditionalover-the-counter (OTC) drug products to the unrestricted aisles andshelves of drug stores and pharmacies. Historically, products containingpseudoephedrine and/or ephedrine were readily available to the generalpublic and served to provide relief for cold, cough, decongestion, andallergy symptoms. Commerce has been severely impeded for these productsdue to governmental controls placed on their sale and distribution in anattempt to mitigate diversion for the production of methamphetamine.When intended for the preparation of methamphetamine, pseudoephedrine orephedrine must be obtained in reasonably pure form prior to the chemicalreduction step of benzylic hydroxyl removal. This chemical reductionstep provides a second active pharmaceutical ingredient,methamphetamine, usually intended for illicit use or for the behavioralact of drug abuse.

Isolation of pseudoephedrine or ephedrine from drug products formulatedwith the insoluble organic acid additional salts of the presentinvention such as pseudoephedrine pamoate or ephedrine pamoate requiretedious and costly multi-step isolation techniques comprising the stepsof:

-   -   a) suspension of the drug product in an aqueous medium;    -   b) careful pH adjustment    -   c) filtration of the insoluble excipients and the pamoic acid        moiety    -   d) extraction of the active ingredient into a water immiscible        solvent;    -   e) washing the water immiscible solvent containing the active        ingredient    -   f) drying the solvent;    -   g) optionally evaporating the solvent to obtain the active        ingredient, or    -   h) optionally precipitating the active ingredient by forming its        mineral acid salt, followed by,    -   i) isolating the active ingredient as its mineral acid salt by        filtration, and    -   j) drying the mineral acid salt,        wherein the excipients may include starch, talc, lactose or        another sugar or sugar derivatives, magnesium stearate, gelatin,        colorants, dyes, flow enhancers, anti-statics, preservatives,        compression aids, buffers and the like. The presence of these        inert ingredients or formulation additives severely complicates        and impedes the isolation of purified pseudoephedrine or        ephedrine employing the processing steps listed above.

An “alkaloid” is an amine nitrogen containing natural product, orsynthetically modified or derivatized natural product, or whollysynthesized analog of a natural product, or an amine containing compoundthat exhibits biological activity in animals or humans. The aminenitrogen can be present as a primary, secondary, tertiary or quaternaryamine moiety and a given compound may contain more than one type ofamine functionality. Examples of these materials are the US DrugEnforcement Agency's (DEA) Form 225 of Schedule I through V controlledsubstances, generally divided between narcotic and non-narcoticmaterials. There are also other compounds applicable to the presentinvention not found on the DEA list or which may be added to it in thefuture. Further, the compounds applicable to the present invention mayarise from plant or animal origin, or may be totally obtained throughhuman effort of design and synthesis. A reference to compound classes(pharmocophores) applicable to the invention are found within Strategiesfor Organic Drug Synthesis, by Daniel Lednicer, published by John Wileyand Sons, Inc.© 1998, Chapters 7 through 13 inclusive and individually,Chapter's 13 and 15. Classes of compounds subject to this inventioninclude but are not limited to opiates, morphinoids, tropinoids,amphetamines, compounds containing a piperidine or substitutedpiperidine sub-structure within the molecule, benzodiazepines,benzazepines, and compounds containing a phenethyl amine or substitutedphenethylamine sub-structure within the molecule. The commoncharacteristic to each compound is the presence of an amine nitrogenwhereby the amine nitrogen is either a primary, secondary or tertiaryamine group and is capable of forming a salt with an inorganic ororganic acid, or combinations thereof. Within the description of theinvention, the term alkaloid or amine may be used interchangeably toidentify a compound possessing, or suspected of possessing, biologicalactivity in humans or animals, in its free base (non-salt form) or in asalt form. The differentiating factor defining the invention is thealkaloid's ability to form an organic acid salt that will retain theexpected biological activity when used as intended for legitimatetherapeutic purposes, but is not readily accessible for abuse byinhalation (smoking), mucosal application, nasal absorption (snorting)or by intravenous injection (shooting).

A “drug substance” is a molecular entity or compound, also known as anactive pharmaceutical ingredient (API) that exhibits biological activityfor the purpose of providing human or animal medication to treatdisease, pain or any medically diagnosed condition. It is possible for adrug substance to be used in combination with one or more different drugsubstances to ultimately impart a biological response in humans oranimals. A drug substance is typically formulated with other,non-biologically active compounds to provide a means of predictable andquantitative dosage delivery, or perhaps to impart acceptable stabilityfeatures to the drug product. What is meant by a drug product is aformulation, mixture or admixture of the drug substance withcombinations of excipients, processing aids, buffers and perhaps otherinert ingredients that allow delivery of the drug substance by theselected delivery mechanism to the patient at a predictable dosage (thecarrier matrix). Various delivery mechanisms include solid oral dosage,for example, pills, tablets, or capsules. Additional delivery systemscan include solution or suspension injection dosage forms (includingdepo drug products), transdermal patches, and nasal or inhalationdevices. The dosage is the actual concentration delivered to thepatient, and depending upon many factors and the actual delivery systemselected, the dosage may be available for essentially immediate release,release over time, or manipulated by additional means for stimulatedrelease such as for example, by irradiation. Immediate release isdefined as a drug substance wherein under simulated gastric conditionsat least 85% is released within 1 hour.

It is a well-known chemical principle that an acid and a base will reactto form a salt. It is sometimes possible to predict the physical andchemical properties of these compounds in generalized concepts such aswhich way a melting point will change compared to the un-reacted acid orbase. Dissolution and dissociation rates of drug salts and theirassociated achievable solution concentrations are substantially lesspredictable when attempting to correlate this experimental data to someanticipated bio-availability of the drug. For instance, at a given pH,an observed dissolution rate and the associated solution concentrationof the drug may be dissociation controlled (i.e. ionization) rather thangoverned strictly by solubility parameters. Indeed, different salts ofthe same amine-containing active ingredient are likely to displaydiverging mechanisms of bio-availability as a function of pH. As such,an evaluation of amine-containing active ingredients and their differentsalts would help elucidate their bio-availability mechanisms. Thisapproach could be incorporated into a broader design feature to addressdrug abuse.

For instance, by manipulating the bio-availability mechanism of aparticular API by incorporating functional properties into the API'ssalt, a design feature is introduced. This feature can also extend toeliminating the ability to simply extract the active ingredient from afinished dosage form and abuse the drug by injection. For illustration,the attempted separation of the active ingredient as the free base fromorally administered pharmaceutical product with the intent for injectionabuse would require filtrations, toxic solvent removal and multipleextraction procedures including careful pH adjustments to separate theamine free base from the pamoic acid component. Without an involved andtechnically sophisticated separation, followed by purification, theadministration of the drug for the behavioral act of abuse isphysically, practically and financially precluded.

Classes of compounds subject to this invention include but are notlimited to opiates, morphinoids, tropinoids, amphetamines, compoundscontaining a pyrrolidine, piperidine or a substituted sub-structure ofeither or both pyrrolidine and piperidine within the molecule,benzodiazepines, benzazepines, and compounds containing a phenethylamine or substituted phenethylamine sub-structure within the molecule.

The opiates, or those compounds isolated from opium, or analogous to theprinciple isolate, morphine, generally serve as narcotic analgesics.Similarly, cocaine, a representative tropinoid, was isolated from cocaleaves, and as a class of compounds exhibit anesthetic qualities.Various amphetamines impact processes of the central nervous system andare often employed as stimulants and appetite suppressants (anorexics).The piperidines and pyrrolidines are often employed as usefulpsychotropic drugs. The benzodiazepines have been employed asantianxiety agents (anxiolytics), as hypnotics and occasionally asmuscle relaxants. Clearly, many synthetic and semi-synthetic compoundsof each of these classes have been prepared and have shown utility in abroad range of therapeutic ailment administration.

A table of controlled substances is readily available on the UnitedStates Drug Enforcement Agency's website at www.DEA.gov. Asrepresentative examples, amines from that table which are applicable tothe present invention, but without restricting the scope of theinvention, include acetorphine, acetylmethadol, allylprodine,alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine,etorphine, heroin, ibogaine, ketobemidone, lysergic acid diethylamide,mescaline, methaqualone, 3,4-methylenedioxyamphetamine,3,4-methylenedioxymethamphetamine, N-ethyl-1-phenylcyclohexylamine,peyote, 1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin,1-{1-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine,cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine, glutethimide,hydrocodone, hydromorphone, levo-alphaaceytlmethadol, levorphanol,meperidine, methadone, morphine, opium oxycodone, oxymorphone, poppystraw, thebaine, amphetamine, methamphetamine, methylphenidate,phencyclidine, codeine, benzphetamine, ketamine, alprazolam,chlorodiazepoxide, clorazepate, diethylpropion, fenfluramine,flurazepam, halazepam, lorazepam, mazindol, mebutamate, midazolam,oxazepam, pemoline, pentazocine, phentermine prazepam, quazepam,temazepam, triazolam, zolpidem, and buprenorphine. Other amines thatreceive considerable legal attention are potential and known precursorsto methamphetamine, specifically, ephedrine and pseudoephedrine.

The Merck Manual of Diagnosis and Therapy, 18^(th) Edition, published bythe Merck Research Laboratories (2006) is an excellent source forcross-referencing the cited drug substances, their derivatives, thevarious classifications and categories of drug substances, and how thesecompounds are employed for beneficial medical purposes. It is a legaldistinction to classify some drugs substances as “controlled substances”as per the DEA's requirements versus the medical benefits availablethrough administration of a specific drug. Within the context of thisinvention, the legal distinction does not limit, or impose limitationsupon the invention. The invention provides a chemical solution to thesocietal need for beneficial medications while preventing the aberranthuman behavior or intention to incorrectly administer, participate insubstance use disorder or to deliberately abuse these drugs. Mostcontrolled substances fall within the following therapeutic categories:anorexics, anxiolytics, analgesics, anesthetics, antihypertensives,anticonvulsants, sedatives, hypnotics and hallucinogens. Of specialinterest are ephedrine (a bronchodilator) and pseudoephedrine (adecongestant), both of which can serve as suitable precursors tomethamphetamine.

The Merck Manual indicates the following opioids have analgesicproperties: codeine, hydrocodone, propoxyphene, fentanyl, hydromorphone,levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone,buprenorphine, butorphanol, nalbuphine, and pentazocine. The Manualfurther lists classes of non-opioid analgesics also applicable to thepresent invention and include: indoles, naphthylalkanones, oxicam,para-aminophenol derivatives, fenamates, pyrazaoles, pyrrolo-pyrroloderivatives, and selective COX-2 inhibitors. Dextromoramide,pentazocine, buprenorphine, alphaprodine phencyclidine, ketobemidone,heroin, allylprodine, acetylmethadol, and anileridine also exhibitanalgesic properties.

The Merck Manual also describes several anesthetic compounds to whichthe current invention is applicable. These compounds include but are notlimited to lidocaine, bupivacaine, tetracaine and epinephrine.

Antipsychotic compounds are prone to abuse or deliberatemis-administration. Classes of these compounds listed in the MerckManual include: phenothiazines, piperidines, piperazines,dibenzoxazepines, dihydroindolones, thioxanthenes, butyrophenones,diphenylbutylpiperidines, dibenzodiazepines, benzisoxzoles,theinobenzodiazepines, dibenzothiazepines, benzisothiazolylpiperazine,and dihydrocarostyrils.

Obesity is often treated with anorexics such as benzphetamine, andsimilar phenethylamine derivatives, for example, phentermine. Othertherapeutic agents for treating obesity include sibutramine, mazindol,diethylpropion and fenfluramine.

With regard to psychiatric disorders, the Merck Manual discusses druguse and the potential for subsequent dependence of: amphetamines,anxiolytics and sedatives (hypnotics), cocaine, gamma hydroxybutyrates,hallucinogens, ketamine, marijuana, methylenedioxymethamphetamine, andopioids. Most interestingly, the Merck Manual states, “Drug abuse isdefinable only in terms of societal disapproval”. The phrase, “substanceuse disorder” is applied concerning children and adolescents usingcontrolled substances whereas, experimental or recreational use ofdrugs, while usually illegal, are the terms used for adult use ofcontrolled substances. The amphetamines include amphetamine andmethamphetamine. The Manual states, “Methamphetamine is the chief typeof amphetamine abuse in North America”. Unfortunately, the cough, coldand sinus medications pseudoephedrine and ephedrine have received closecommercial scrutiny because of the ability to convert these compounds tomethamphetamine. Anxiolytics include the barbiturates andbenzodiazepines. The latter category includes drug substances such asalprazolam, lorazepam and triazolam. Other anxiolytics includehalazepam, oxazepam, prazepam, diazepam, chlorazepate andchlordiazepoxide. Cocaine can cause euphoric excitement or schizophreniclike symptoms whereas ketamine exhibits anesthetic properties.Methylenedioxymethamphetamine produces a feeling of excitement,disinhibition and accentuates physical sensation.

The Merck Manual reports that learning and developmental disorders areoften treated with the controlled substances, methylphenidate ordextroamphetamine.

Compounds included within the sedative or hypnotic therapeutic categoryinclude but are not limited to: quazepam, temazepam, triazolam,zolpidem, glutethimide and flurazepam.

Compounds included within the hallucinogenic category includeN-ethyl-1-phenylcyclohexylamine, peyote,1-(1-phenylcyclohexyl)pyrrolidine, psilocybin, psilocin, mescaline,1-[1-(2-thienyl)-cyclohexyl]piperidine, bufotenine, ibogaine, andlysergic acid diethylamide.

With respect to a specific list of controlled substances, the list ismaintained by the DEA and as a legal action occurring through dueprocess of law, compounds may be added to or deleted from the list. Incontext of this invention, the compounds of interest may be categorizedand/or classified according to a number of names as the precedingdiscussion indicates. Specific compounds will fall within a generalclass and to that particular class, new derivatives may be synthesizedyielding similar therapeutic indications and consequently, the potentialfor abuse. Additionally, dosage levels of a particular compound may alsoimpact its therapeutic indication. By way of example, midazolam has atherapeutic indication as an anesthetic, anticonvulsant, sedative andhypnotic.

The basic physical and chemical properties of these amines/alkaloids areconsistent with amines which receive considerably less attention andwhich are typically not prone to abuse. It is well understood that thepKa values of the conjugate acid for each amine confirms their abilityto produce organic acid addition salts. For comparative purposes betweenamines, a higher pKa (amine conjugate acid) indicates a lower basicitystrength for the amine. Consequently, and by way of example withoutlimiting the scope, the controlled substances listed, demonstrate thefundamental requirement (amine basicity) for producing an organic acidaddition salt and indeed, amines having a conjugate acid pKa greaterthan approximately 1.5 are receptive to pamoate salt formation.

Interestingly, pamoate salts have been shown to exhibit polymorphism asdescribed in co-pending U.S. patent application Ser. No. 11/595,379filed Nov. 10, 2006 titled “Physical States of a Pharmaceutical DrugSubstance”, the disclosure of which is totally incorporated herein byreference. This property of a compound is its ability to solidify indifferent crystal structures, habits or lattices to yield polymorphs.Indeed, for a drug substance that exhibits polymorphism, differentsituations may exist: the material may solidify and be isolated from thereaction as 1) an amorphous solid; 2) a single polymorph may beobtained, or 3) a mixture of polymorphs and 4) combinations of theprevious three possibilities. Therefore it is important, whenpolymorphism is suspected, to deliberately attempt to prepare, isolateand characterize the different polymorphs by techniques sufficient todifferentiate between amorphous material and individual polymorphs ortheir mixtures. Often differential scanning calorimetry (DSC) can beemployed to identify or monitor the creation of polymorphs. Indeed, whena salt candidate's stability profile can be correlated to a specificpolymorph, appropriate synthetic process development activities candefine the controlling conditions necessary to yield the single, desiredpolymorph or some other defined ratio of polymorphs exhibiting anacceptable stability profile.

API salts and their polymorphs often exhibit different dissolutioncharacteristics. For instance the rate of dissolution is pH dependent,and therefore yields a different pharmacokinetic profile and/ortherapeutic efficacy. Sometimes, a given drug product formulationexpertise or technology can dominate any biological effects the API saltand/or polymorph present. Conversely, drug product formulation and theresulting mechanical properties of a tablet, capsule or bead can bedominated by the physical behavior of the API salt and/or its particularcrystal structure. It is not unusual that difficult trade-offs must bemade between the ease of manufacture of the drug product and thepharmacokinetics desired.

Drug product formulation can impact the pharmacokinetics of an API saltcandidate (and potential polymorph) by a host of technologies, includingbut not limited to, preparing formulated beads, different sized beads,coated beads, combinations of various bead technologies, formulatedmatrix systems, addition of hydrophobic layers to tablets, capsules orbeads (for example, as a control mechanism to limit the dissolution rateof hydrophilic gelatin capsules), coated tablets and capsules, capsulesfilled with beads, and different mixtures of beads with differentcoatings. These formulation techniques make available a wide range ofdrug product properties including, but not limited to, slow release,controlled release, and extended release drug pharmacokinetics. Theseactivities are dependent upon the API salt selected (and potentialpolymorph issues) because of the salt's dissolution profile at the pHwhere drug release is to occur (for liberation of the API from its saltform). In fact, different API salts and formulation techniques can beselected based on where the desired release is to occur in thegastrointestinal tract and the formulator can use the API salt's pKa,solubility, melting point, shape and particle size as primary factors toutilize, moderate or overcome localized insolubility through the use offormulation techniques.

EXPERIMENTAL Experimental Methods Differential Scanning Calorimetry

Samples were evaluated using a Differential Scanning Calorimeter from TAInstruments (DSC 2010). Prior to analysis of samples, a single-pointcalibration of the TA Instruments DSC 2010 Differential ScanningCalorimeter (DSC 2010) with the element indium as calibration standard(156.6±0.25° C.) was completed.

Infrared Spectroscopy

IR Spectra were obtained in a KBr disc using a Perkin Elmer Spectrum BXFourier Transform Infrared Spectrophotometer.

Powder X-Ray Diffraction (PXRD)

Powder X-Ray diffraction patterns were acquired on a Scintag XDS2000powder diffractometer using a copper source and a germanium detector.

High Pressure Liquid Chromatography (HPLC)

HPLC analyses were performed on a Waters 2695 HPLC system equipped witha Waters 2996 photo diode array detector.

Dissolution

Dissolution testing was performed using a Distek Dissolution System 2100consisting of six 1000 mL dissolution vessels with covers containingsampling ports, six stainless steel paddles and spindles, RPM controlunit, and a Distek TCS0200C Water Bath, Temperature Controller Unit.

EXAMPLES Example 1 Preparation of Phentermine Pamoate

Phentermine HCl (37.3 g) was suspended in USP H₂O (700.0 g) and stirredto achieve a solution (0.05 g/g) and a pH 5.3. The solution wastransferred to a metered addition funnel. A solution of disodium pamoate(45.0 g) was prepared by dissolving in USP water (902.0 g) to give aclear solution at a pH 10.4. The solution was adjusted to about pH 9.4with 0.2N HCl and clarified by solution filtration. At 20° C., thePhentermine HCl solution was added to the stirred disodium pamoatesolution at a controlled rate over about 2.5 hours and the additionfunnel rinsed with USP H₂O (20.0 g) into the reaction mixture. Themixture was stirred for 1 h then warmed to 70° C. where moreprecipitation was observed. The mixture was heated from about 70° C. to95° C. over about 1 h then cooled. Solids were collected by filtrationand washed with USP H₂O (3×200 g) and dried on a vacuum Buchner forabout 3 h. The solids collected (83.5 g) were transferred to a dryingoven (50-55° C., vacuum/N₂ sweep) and dried about 48 h to givePhentermine Pamoate (64.7 g, 94.2%). The pamoate was characterized byDSC (FIG. 1), FTIR (FIG. 4) and PXRD (FIG. 7).

Example 2 Preparation of Ephedrine Pamoate

Ephedrine Hydrochloride (6.1 g) was stirred in USP water (45.0 g) toyield a solution pH of about 4.9. In a separate flask a disodium pamoate(6.5 g) solution was prepared using USP water (54.0 g) to yield asolution pH of about 9.5. The ephedrine HCl solution was transferred toa metered addition funnel and added to the disodium pamoate solutionover approximately 1 h. When about one-half of the addition wascompleted, the solution became opaque. USP water (2.6 g) was used torinse in the residue from the addition funnel. The opaque mixture washeated from about 26° C. to near 80° C. The reaction was stirred atabout 80° C. for approximately 4.5 h. A thick residue settled in thereaction vessel as the solution cooled. The solution was decanted andthe residue transferred to drying dishes. The residue was dried at about100° C. under vacuum (nitrogen sweep) for about 5.5 h. Drying wascontinued for about 66 h, the solid ground with a mortar and pestle togive a dense powder (4.2 g, 39%). and a DSC analysis indicated a clearmelt (T_(max) 243.4° C., T_(onset) 227.7° C., and heat of fusion 142.2J/g).

Example 3 Alternate Preparation of Ephedrine Pamoate

Ephedrine Hydrochloride (7.1 g) was stirred in methanol (62.6 g).Disodium pamoate (8.0 g) was stirred in USP water (71.0 g) and adjustedto about pH 9.5. The methanolic ephedrine hydrochloride solution wasadded to the disodium pamoate solution over a period of about 1.75 h.The reaction solution was heated to about 60° C. for around 4.5 h thencooled. The reactor was equipped with a distillation head and aqueousmethanol was removed by heating. The opaque mixture was cooled and aresidue settled to the bottom of the reaction vessel. The solution wascarefully decanted and the residue was transferred to a drying dish. Thematerial was placed in a vacuum drying oven (103° C.) for 24 h with anitrogen sweep. Ephedrine Pamoate was obtained as a solid, 8.4 g (66.6%)2:1 ephedrine pamoate (by HPLC assay) and characterized by DSC (FIG. 2),FTIR (FIG. 5) and PXRD (FIG. 8).

Example 4 Preparation of Pseudoephedrine Pamoate

Disodium pamoate (10.4 g) was dissolved in USP water (73.5 g) andfiltered to clarify. The filtrate was returned to a rinsed reactoremploying a water rinse (15 g). The solution of disodium pamoateexhibited a pH of about 9.5. Pseudoephedrine HCl (9.3 g) in USP water(53.1 g) was prepared and exhibited a pH of about 6.3. Thepseudoephedrine HCl solution was added to the disodium pamoate solution.As the addition continued, the oily mixture became opaque. Aftercomplete addition (˜1 h), the residue in the addition funnel was rinsedinto the reaction vessel with USP water (5.0 g). The mixture was heatedat about 84° C. for approximately 3.25 h. The mixture was then cooledovernight and solids were collected by filtration. The filter cake waswashed with USP water (3×30 g) and dried in a vacuum oven (98-102° C.)for about 5.2 h with a nitrogen sweep. After cooling, the finelypowdered 2:1 (by HPLC) pseudoephedrine pamoate solids (15.9 g, 87%) wascharacterized by DSC (FIG. 3), FTIR (FIG. 6) and PXRD (FIG. 9).

Example 5 Preparation of Benzphetamine Pamoate

To a solution containing disodium pamoate (19.1 g) in water (218.0 g)was added as needed dilute HCl or NaOH solution to adjust the solutionto about pH 9.4. To a second solution of benzphetamine HCl (24.3 g) inwater (211.0 g) was added dilute HCl or NaOH solution to adjust thesolution to about pH 4.5. The benzphetamine HCl solution was added tothe disodium pamoate solution over a period of about 3 h. The mixturewas stirred and held at about 53° C. for at least 18 h. The mixture wascooled to below 25° C. and the solids were collected by filtration. Thesolid cake was washed with USP purified water. The wet cake was dried at70° C. under reduced pressure to yield a solid (30.0 g). The 2:1benzphetamine pamoate by HPLC assay was characterized by DSC (FIG. 10),FTIR (FIG. 11) and PXRD (FIG. 12).

Example 6 Solubility Recovery Comparison of Selected Amine Salts

A comparison of pseudoephedrine as its pamoate salt and as ithydrochloride was performed at 37° C. Each salt was tested for itssolubility recovery at pH 4.5 and pH 7.0. For comparison equivalency,the amount of pamoate salt was adjusted to account for the molecularweight difference between the pamoate and the hydrochloride such thatequal amounts of pseudoephedrine were compared at each pH condition.

A flask containing USP H₂O (10.0 mL at pH 4.5 having used HCl to adjust)was warmed to 37° C.±2° C. in a water bath. Pseudoephedrine HCl (1.0 g)was added to the solution at 37° C.±2° C. A visual observation indicatedthe immediate dissolution of about ⅔ of the bulk solids. Magneticstirring was initiated and a solution was observed. The solution wasstirred for 31 min then filtered. No solids were collected and flask wasrinsed to the filter with USP H₂O (pH 4.5) (2×5.0 g). PseudoephedrineHCl was completely soluble at pH 4.5.

In a second flask containing USP H₂O (10.0 mL at pH 4.5 having used HClto adjust) was warmed to 37° C.±2° C. in a water bath. Pseudoephedrinepamoate (1.8 g) was added to the solution. The pamoate salt, as a solid,floated on top of the water and did not wet. Magnetic stirring wasinitiated and some solids were pulled below the surface and stirred.Approximately ½-⅔ of the solids remained above the water surface and thethermometer was used to push the remaining solids below the watersurface. A bi-phasic mixture was observed which was stirred for 32 minand then filtered to collect the solids. The flask contents were rinsedto the filter with USP H₂O (pH 4.5) (3×5.0 g). The solids were driedunder vacuum then transferred to a drying pan and into a vacuum oven(80±2° C.) under N₂. After 19.75 h, the solids were removed to cool andweighed yielding a mass recovery of peudoephedrine pamoate (1.76 g)(98%).

Pseudoephedrine pamoate was insoluble at pH 4.5.

A similar set of experiments was conducted whereby a flask containingUSP H₂O (10.0 mL at pH 7.0 having used HCl and NaOH to adjust) waswarmed to 37° C.±2° C. in a water bath. Pseudoephedrine HCl (1.02 g) wasadded to the solution at 37° C.±2° C. A visual observation indicated theimmediate dissolution of about ⅔ of the bulk solids. Magnetic stirringwas initiated and a solution was observed. The solution was stirred for31 min then filtered. No solids were collected and flask was rinsed tothe filter with USP H₂O (pH 7.0) (2×5.0 g). Pseudoephedrine HCl wascompletely soluble at pH 7.0.

In a second flask containing USP H₂O (10.0 mL at pH 7.0 having used HCland NaOH to adjust) was warmed to 37° C.±2° C. in a water bath.Pseudoephedrine pamoate (1.80 g) was added to the solution. The solidpseudoephedrine pamoate floated on top of the water and did not wet.Magnetic stirring was initiated and some solids were pulled below thesurface and stirred. Approximately ½-⅔ of the solids remained above thewater surface and the thermometer was used to push the remaining solidsbelow the water surface. A bi-phasic mixture was observed. The mixturewas stirred for 31 min and then vacuum filtered to collect the solids.The flask contents were rinsed to the filter with USP H₂O (pH 7.0) (3×5g). The solids were dried under vacuum then transferred to a drying panand into a vacuum oven (80±2° C.) under N₂. After 14.75 h, the solidswere removed to cool and weighed to yield a mass recovery ofpseudoephedrine pamoate (1.76 g) (98%). Pseudoephedrine pamoate wasinsoluble at pH 7.0.

In a similar fashion, the recovery solubility comparisons were performedon benzphetamine, ephedrine, phentermine and imipramine as theirhydrochloride and pamoate salts at the two pH conditions of 4.5 and 7.0at 37° C. Imipramine xinafoate and salicylate were also tested underthese conditions. The results from each of these comparative studies aresummarized in the table below. It was consistently observed that thehydrochloride salt yielded a complete solution whereas the pamoate,xinafoate and salicylate within experimental error of handling andrecovery manipulations, demonstrated insolubility at pH 4.5 and 7.0.

Drug pH % Recovery Phentermine Pamoate 4.5 98.4 Phentermine HCl 4.5 0Phentermine Pamoate 7.0 97.3 Phentermine HCl 7.0 0 Ephedrine Pamoate 4.594.4 Ephedrine HCl 4.5 0 Ephedrine Pamoate 7.0 94.4 Ephedrine HCl 7.0 0Pseudoephedrine Pamoate 4.5 98.9 Pseudoephedrine HCl 4.5 0Pseudoephedrine Pamoate 7.0 97.8 Pseudoephedrine HCl 7.0 0 BenzphetaminePamoate 4.5 91.1 Benzphetamine HCl 4.5 0 Benzphetamine Pamoate 7.0 92.7Benzphetamine HCl 7.0 0 Imipramine HCl 4.5 0 Imipramine Xinaforate 4.597.0 Imipramine Salicylate 4.5 104 Imipramine HCl 7.0 0 ImipramineXinafoate 7.0 97.0 Imipramine Salicylate 7.0 104

Example 7 Preparation of Imipramine Xinafoate

To a solution containing 7.7 g of 3-hydroxy-2-napthoic acid in 75.0 g ofUSP water was added as necessary dilute HCl or NaOH solution to adjustthe solution to about pH 9.4. To a second solution of 13.6 g ofimipramine HCl in 100.0 g of USP water was added as necessary dilute HClor NaOH solution to adjust the solution to about pH 4.5. The imipramineHCl solution was added to the 3-hydroxy-2-napthoic sodium salt solutionover a period of about 2 h. The mixture was stirred and held at around50° C. for at least 18 h. The mixture was cooled to below 25° C. and thesolids were collected by filtration. The solid cake was washed with USPwater (2×100 g). The solid cake was dried at 105° C. under vacuum toyield a powder (12.7 g) and characterized by DSC (FIG. 13), FTIR (FIG.14) and ¹H NMR (FIG. 15).

Example 8 Preparation of Imipramine Salicylate

Sodium Salicylate (16.4 g) in USP water (118.0 g) was stirred at 20° C.in a 1 L reactor. After 15 min, the solution was checked and exhibitedpH 6.23. In a Imipramine HCl (31.7 g) in USP water (320.0 g) was stirredat 22° C. in a 500 mL reactor until a solution was observed (>20 min).The Imipramine HCl solution was checked and exhibited a pH 4.54. TheImipramine HCl solution was added via metered addition funnel to thesodium salicylate solution at 20° C. over 1.75 h. The reactor andaddition funnel was rinsed to the reaction with USP water (20.0 g). Thereaction mixture was heated from about 20° C. to about 50° C. for 1.2 h.The mixture was heated to about 62° C. for 17 h. Solids were collectedby filtration of the mixture at 50° C. Residue was rinsed from thereactor to the filter with USP water (4×110.0 g). After drying on thefilter for 1 h, solids were dried at about 65° C. to about 78° C. forapproximately a day. Imipramine salicylate, mp 141-143.6° C. (39.8 g,95.1%). Recrystallization of imipramine salicylate from a solution ofethanol-water (98/2) provided solid, mp 142.2-144.2° C. The DSCthermogram (FIG. 16), FTIR analysis (FIG. 17) and ¹H NMR spectra (FIG.18) were consistent with the expected structure.

Example 9 Dissolution Testing Procedure

Dissolution testing was performed according to the FDA's Guidance forIndustry document entitled, “Waiver of In Vivo Bioavailability andBioequivalence Studies for Immediate-Release Solid Oral Dosage FormsBased on a Biopharmaceuticals Classification System and following therecommendations under section III C titled “Determining Drug ProductDissolution Characteristics and Dissolution Profile Similarity”. Acomparison dissolution test was performed for each active ingredient'shydrochloride salt versus its pamoate salt with concentrations adjustedfor molecular weight differences. This adjustment provided an equalconcentration of active ingredient (calculated as the free base) forboth the hydrochloride and pamoate salts. A similar calculation andcharge adjustment was performed in the case of xinafoate and salicylatesalt comparisons to the corresponding hydrochloride salt.

The Distek Dissolution System was arranged in an Apparatus IIconfiguration as per United States Pharmacopeia dissolution testingprocedure USP <711> employing paddles and a 50 RPM spindle speed. Thewater bath temperature was set and controlled at 37±1° C.

The dissolution tests on drug hydrochlorides and the drug pamoates,xinafoate, and salicylate were performed as separate experimental sets.Each experimental set was subjected to simulated gastric conditions byemploying a standardized (and traceable) buffered 0.1 N HCl solutionsupplied by VWR.

Each test sample was filled into a clear gelatin capsule (Capsuline Size“2”). The pharmaceutical grade gelatin capsules are derived from bovineraw materials from BSE-free countries. The gelatin is 100% HIDE gelatin.A wire (˜1.7-2.0 g) was coiled around each capsule to assure the capsuledid not float in the test medium. The amount of each API filled into anindividual capsule was determined based on the highest unit doseavailable for a commercialized drug product. By way of example, thehighest dose commercialized drug product containing the activepharmaceutical ingredient phentermine hydrochloride contains 37.5 mg ofthe active ingredient as its hydrochloride. The following tablesummarizes the amount of each active ingredient loaded into a capsule.The amounts of the active ingredient for the pamoates, xinafoate andsalicylate salts have been adjusted for their higher molecular weightcontribution and for the actual stoichiometry within the salt. Forinstance, the pamoates herein exist as a 2:1 complex of amine-containingactive ingredient to pamoate moiety.

MW Weight (Active as Free Drug Salt g/mol (mg) Base) (mg) DrugHydrochloride Ephedrine Hydrochloride 201.69  47.6  39.4 Pseudoephedrine201.69  60.6  49.6 Hydrochloride Phentermine Hydrochloride 185.70  37.5 30.1 Benzphetamine 275.86  50.3  40.3 Hydrochloride ImipramineHydrochloride 316.88 150.7 133.1 Drug Salt (Pamoate, Xinafoate,Salicylate)* Ephedrine Pamoate 717.98  85.4  39.2 PseudoephedrinePamaote 717.98 107.0  49.2 Phentermine Pamoate 658.80  66.5  30.8Benzphetamine Pamoate 866.32  78.5  43.3 Imipramine Xinafoate 468.16221.0 132.1 Imipramine Salicylate 419.30 198.0 132.2 Imipramine Pamoate949.18 225.0 132.7 *All Pamoate Salts are 2:1, Xinafoate Salt is 1:1,Salicylate Salt is 1:1, and Hydrochloride Salts are 1:1

Prior to use, the 0.1N HCl solution was warmed to 38-42° C. withadequate stirring and then degassed for 30 minutes with helium passedthrough a sparge stone attached to Tygon tubing. The degassed bufferedsolution was dispensed into each of five dissolution vessels (900mL/vessel) using a volumetric flask. The vessels were immersed in theconstant temperature bath and allowed to reach thermal equilibrium(37±1° C.). A single capsule (with wire weighting) and containing aspecified drug salt was then added to each vessel, the paddles andspindles lowered into the solution and agitation initiated at 50 RPM.The covers with sampling ports were then placed on each vessel. Samplingwas performed at regular time intervals on each vessel using a samplingsyringe dedicated to each vessel. At each sampling time point about 10mL of solution was removed from the vessel and filled into a test vialfor HPLC analysis.

Example 10 Dissolution Monitoring by HPLC

Drug dissolution assays at specified time intervals were determined by ahigh pressure liquid chromatography (HPLC) method employing a WatersAtlantis column (dC18, 5 micron, 4.6×150 mm), or equivalent. The HPLCsystem was a Waters 2695 HPLC system equipped with a Waters 2996 photodiode array detector (detection wavelength: 265 nm extracted; 215 nmextracted). The eluant consisted of mobile phase A (0.1% TFA in water)and mobile phase B (acetonitrile). The gradient elution conditions wereas tabulated below.

Gradient Elution Table Time min % A % B 1 80 20 2  6.00 80 20 3 10.00 5248 4 25.00 52 48 5 25.10 80 20 6 33.00 80 20

The drug hydrochlorides were employed as reference comparisons for thedissolution of the corresponding organic acid addition salt of the drug.Reference standards are available from the United States Pharmacopeia;imipramine hydrochloride employed as reference standard was used “as is”and was available from Sigma-Aldrich Catalog #10899. Proceeding, 30-45mg of the drug hydrochloride reference standard was accurately weighedinto a 100 mL volumetric flask and diluted to volume with a previouslyprepared sample diluent consisting of a filtered 8:2 water:acetonitrilesolution. Samples of the dissolution trial solutions were obtained attimed intervals and diluted prior to analysis to obtain targetedconcentrations of approximately 45 micro grams/mL-75 micro grams/mL ofactive pharmaceutical ingredient (API). The prepared samples were thenfiltered through a 0.45 micron filter directly into an HPLC vial,labeled and loaded for injection into the HPLC system.

HPLC data collection was performed and concentrations determined foreach dissolution time interval for each drug substance tested.Concentration assays were determined as a weight/weight percent based onthe assay obtained from the reference standard. The data was plotted asa function of percent unit dose released versus the sampling intervaltime (FIGS. 19 through 25) wherein the percent unit dose releasedcorresponds to a mass assay of the active species found by HPLC analysisof each dissolution time point divided by the available mass initiallydelivered to the test solution in the capsule. Pairs of data sets wereplotted to assess the behavior of the hydrochloride salts versus theorganic acid addition salts of the present invention under simulatedgastric conditions. Similarly, the dissolution data from HPLC analyseswas plotted along with the mass recovery data for each amine saltobtained at pH 4.5 and 7.0 (Example 6). Here also, data set pairs wereplotted to assess the behavior of the hydrochloride salts versus theassociated organic acid addition salts over a pH range encompassinggastric and mucosal conditions (FIGS. 26-32).

Example 11 Solubility Evaluation of the Pseudoephedrine Pamoate

The solubility of pseudoephedrine pamoate was evaluated in each ofisopropanol, acetone and toluene. About 0.5 grams of the salt was addedto approximately 5.0 grams of each solvent. The samples were stirred atroom temperature for about 15 minutes, filtered and dried to determine amass percent recovery of the salt. The filtrates appeared clear andwithout color with the exception of the acetone filtrate exhibiting somecolor. The mass recoveries for the salt from each solvent were: 97%(isopropanol); 92% (acetone); 99% (toluene). Similar results wereobtained for the solubility evaluation of ephedrine pamoate.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

Claimed is:
 1. A method of administering an amine-containingpharmaceutically active compound formulation comprising: a) providingsaid amine-containing pharmaceutically active compound formulation bypreparing an organic acid salt of said compound wherein said organicacid addition salt exhibits sustained release of said compound from saidorganic acid salt wherein said organic acid salt of said compound isselected from the group consisting of: ephedrine pamoate characterizedby a method selected from the group consisting of: a DSC thermogram ofFIG. 2, and a PXRD of FIG. 8; pseudoephedrine pamoate characterized by amethod selected from the group consisting of: a DSC thermogram of FIG.3, and a PXRD of FIG. 9; benzphetamine pamoate characterized by a methodselected from the group consisting of: a DSC thermogram of FIG. 10 and aPXRD of FIG. 12, and phentermine pamoate characterized by a methodselected from the group consisting of: a DSC thermogram of FIG. 1, and aPXRD of FIG. 7; b) preparing an oral dose formulation comprising saidorganic acid salt of said compound and a matrix; c) administering saidoral dose formulation to a patient for oral ingestion of said oral doseby said patient; and d) wherein upon use of said organic salt of saidcompound absent said matrix by said patient via a mucosal membrane otherthan gastrointestinal mucosal membranes said amine-containingpharmaceutically active compound is not bio-available.
 2. The method ofadministering an amine-containing pharmaceutically active compound ofclaim 1 in a form selected from the group consisting of a tablet, acapsule, a caplet, and an oral suspension.
 3. The method ofadministering an amine-containing pharmaceutically active compound ofclaim 1 wherein said pharmaceutically acceptable organic acid additionsalt of an amine containing pharmaceutically active compound has a phasetransition temperature of at least 100° C.
 4. The method ofadministering an amine-containing pharmaceutically active compound ofclaim 1 wherein said pharmaceutically active compound is bio-unavailablewhen exposed to non-gastrointestinal mucosal membranes and exhibitsrecovery from aqueous solution at about pH 4.5 of at least 85 weightpercent.
 5. The method of administering an amine-containingpharmaceutically active compound of claim 1 wherein saidpharmaceutically active compound is bio-unavailable when exposed tonon-gastrointestinal mucosal membranes and exhibits recovery fromaqueous solution at about pH 7.0 of at least 85 weight percent.
 6. Themethod of administering an amine-containing pharmaceutically activecompound of claim 1 designed for immediate release in thegastrointestinal tract and for essentially non-release in the mucosalmembranes.
 7. The method of administering an amine-containingpharmaceutically active compound of claim 1 administered for at leastone purpose selected from anti-convulsant, anti-depressant, analgesic,anesthetic, anxiolytic, psychotropic, hallucinogenic, hypnotic, andanorexic.
 8. The method of administering an amine-containingpharmaceutically active compound of claim 1 administered to treat one ofcough, cold and sinus congestion.